Cocaine dependence continues to represent a major social and medical problem in the United States. Effective behavioral therapies have been developed, but failure rates remain high, and effective pharmacotherapies are needed. Most efforts to develop medications have targeted cocaine dependence in general. This proposal pursues an alternative approach, that greater success would be achieved by focusing treatment on specific subgroups, such as patients with co-occurring depression. Depression is prevalent among cocaine dependent patients and associated with poor outcome. A placebo-controlled trial of the antidepressant medication, desipramine, in selected depressed cocaine abusers, conducted under this Project, yielded encouraging results in that depressive symptoms responded to desipramine treatment, and depression improvement was correlated with reduction in cocaine use. However, a direct effect of medication on cocaine use could not be demonstrated, and few patients achieved abstinence. Clinical wisdom, and the results of related trials among alcoholics, suggest medication effects are strongest when depression can be diagnosed after persisting during a period of abstinence in hospital, thus representing a primary rather than a substance-induced depression. However, such hospitalization is not practical in most instances, and clinicians have lacked tools for rapidly establishing abstinence on an outpatient basis. Further, the impact of antidepressant medication, particularly on cocaine use, might be enhanced by combining medication with voucher incentives contingent on abstinence, in the trial now proposed, cocaine dependent outpatients, meeting DSM-IV criteria for current major depression, will first enter an abstinence-induction period of 14days, with a high value voucher incentive regimen designed to induce initial abstinence. Patients will then be stratified according to whether their depression improves in response to the initial abstinence-induction procedure, and randomly assigned to the antidepressant medication venlafaxine, or placebo, for a 12-week double-blind trial. During the trial they will continue to receive vouchers contingent on abstinence according to a low cost intermittent reinforcement schedule developed for implementation in community treatment settings. The following specific aims will be addressed: Specific Aim #1: To determine in cocaine dependent patients with depressive disorders whether venlafaxine in the context of voucher incentives is superior to placebo in improving depression and cocaine use. Specific Aim #2: To determine whether the effect of venlafaxine on depression and cocaine use outcome is restricted to patients whose depression persists during an initial period of abstinence supported by voucher incentives.